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These microbial communities contribute to immune regulation, barrier integrity, and defence against pathogens. Disruptions in this equilibrium can precipitate dermatological disorders such as acne vulgaris, which affects millions of adolescents and adults worldwide. This chronic inflammatory disorder of the pilosebaceous unit is driven by microbial dysbiosis, hyperkeratinisation, sebum overproduction, and inflammation. This review synthesizes data from over 100 sources to examine the interplay between the skin microbiome and acne pathogenesis, and to compare synthetic treatments, including retinoids, antibiotics, and hormonal therapies, with natural approaches such as polyphenols, minerals, and resveratrol. The analysis highlights the therapeutic convergence of traditional pharmacology and bioactive natural compounds, proposing microbiome-conscious and sustainable strategies for future acne management.<\/jats:p>","DOI":"10.3390\/molecules30244684","type":"journal-article","created":{"date-parts":[[2025,12,8]],"date-time":"2025-12-08T10:35:51Z","timestamp":1765190151000},"page":"4684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Rebalancing the Skin: The Microbiome, Acne Pathogenesis, and the Future of Natural and Synthetic Therapies"],"prefix":"10.3390","volume":"30","author":[{"given":"Maria Beatriz","family":"Oliveira","sequence":"first","affiliation":[{"name":"Centre for Animal Science Studies (CECA), Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, 5050-313 Porto, Portugal"},{"name":"Associated Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0018-9363","authenticated-orcid":false,"given":"Ana Colette","family":"Maur\u00edcio","sequence":"additional","affiliation":[{"name":"Centre for Animal Science Studies (CECA), Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, 5050-313 Porto, Portugal"},{"name":"Associated Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisbon, Portugal"},{"name":"Department of Veterinary Clinic, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, 5050-313 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5834-6141","authenticated-orcid":false,"given":"Ana Novo","family":"Barros","sequence":"additional","affiliation":[{"name":"Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), Inov4Agro, University of Tr\u00e1s-os-Montes and Alto Douro (UTAD), 5000-801 Vila Real, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8221-419X","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Botelho","sequence":"additional","affiliation":[{"name":"Centre for Animal Science Studies (CECA), Institute of Sciences, Technologies and Agroenvironment (ICETA), University of Porto, 5050-313 Porto, Portugal"},{"name":"Associated Laboratory for Animal and Veterinary Science (AL4AnimalS), 1300-477 Lisbon, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Chen, Y., Knight, R., and Gallo, R.L. 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